The effect of ivabradine therapy on heart failure patients with reduced ejection fraction: a systematic review and meta-analysis
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Background Ivabradine is currently indicated to lower heart rate in Heart Failure with Reduced Ejection Fraction (HFrEF) patients. However its effect apart from beta-blockers is not clear. Aim of the review To study the additional effect of ivabradine, apart from the effect of beta-blockers, on cardiovascular death, all-cause mortality, hospitalization due to HF and heart rate in HFrEF population. Method Electronic searches were conducted up to June 2016 to include randomized controlled trials where ivabradine was compared to a control group. Relative risks RRs and their 95% confidence intervals (CI 95%) were pooled and the random and fixed effect were used to summarize the results according to heterogeneity levels. Heterogeneity among studies was measured by the I-squared statistic Results Of 1790 studies, seven met the inclusion criteria for the systematic review and meta-analysis. The population consisted of 17,747 patients. Risk of bias was generally high for beta-blocker doses lower than recommended. Interventions lasted 1.5–22.9 months and pooled relative risks RR (95%) for all-cause mortality, cardiovascular death and hospitalization for HF were 0.98 (0.90–1.06); 0.99 (0.91–1.08); and 0.87 (0.68–1.12) respectively. Heart rate (CI 95%) decreased by 8.7 (6.37–11.03) beats per minute with ivabradine compared to the control group. Subgroup analysis by beta-blocker dose showed that for patients on recommended treatment (at least 50% of the beta-blocker target dose), heart rate (CI 95%) decreased by 4.70 (3.67–5.73), whereas for patients not on recommended treatment or with unreported dose, heart rate decreased by 8.60 (8.13–9.08). Conclusion Ivabradine significantly reduced heart rate and its additional effect on heart rate appears to be inversely correlated with the dose of beta-blocker. It showed no significant effect for all-cause mortality, cardiovascular death and hospitalization due to HF. Unreported beta-blocker doses and beta-blocker doses lower than recommended limited the conclusions.
KeywordsBeta-blockers Heart failure Heart rate Ivabradine Left ventricular dysfunction Systematic review
We would like to thank the graduate program in health sciences of Pontifícia Universidade Católica do Paraná (PUCPR).
Source data for this systematic review were collected and analyzed by the independent authors. All cost of the research was funded by the authors.
Conflicts of interest
Camila Hartmann has received speaker’s fees from Cristália. Lídia Zytynski Moura has received speaker honoraria and research support from Servier and EMS. Natasha Ludmila Bosch, Luara de Aragão Miguita, Elise Tierie, and Cristina Pellegrino Baena declare no potential conflicts of interest that might be relevant to this manuscript.
- 8.Cappato R, Castelvecchio S, Ricci C, Bianco E, Vitali-Serdoz L, Gnecchi-Ruscone T, et al. Clinical efficacy of ivabradine in patients with inappropriate sinus tachycardia: a prospective, randomized, placebo-controlled, double-blind, crossover evaluation. J Am Coll Cardiol. 2012;60(15):1323–9.CrossRefPubMedGoogle Scholar
- 10.Higgins JPT, Green S (eds). Cochrane handbook for systematic reviews of interventions version 5.1.0 [updated March 2011]. The Cochrane Collaboration. 2011. www.handbook.cochrane.org.
- 13.Sarullo FM, Fazio G, Puccio D, Fasullo S, Paterna S, Novo S, et al. Impact of “off-label” use of ivabradine on exercise capacity, gas exchange, functional class, quality of life, and neurohormonal modulation in patients with ischemic chronic heart failure. J Cardiovasc Pharmacol Ther. 2010;15(4):349–55.CrossRefPubMedGoogle Scholar
- 22.Hasenfuss G, Holubarsch C, Hermann HP, Astheimer K, Pieske B, Just H. Influence of the force-frequency relationship on haemodynamics and left ventricular function in patients with non-failing hearts and in patients with dilated cardiomyopathy. Eur Heart J. 1994;15(2):164–70.CrossRefPubMedGoogle Scholar
- 24.Hidalgo FJ, Anguita M, Castillo JC, Rodríguez S, Pardo L, Durán E, et al. Effect of early treatment with ivabradine combined with beta-blockers versus beta-blockers alone in patients hospitalised with heart failure and reduced left ventricular ejection fraction (ETHIC-AHF): a randomised study. Int J Cardiol. 2016;217:7–11.CrossRefPubMedGoogle Scholar